Glucocorticoid resistance in Crohn's disease and ulcerative colitis: an association study investigating GR and FKBP5 gene polymorphisms

Abstract

The aim of this study is to investigate the role of single-nucleotide polymorphisms (SNPs) of the glucocorticoid receptor (GR) and of the related co-chaperone FKBP5 genes in the development of glucocorticoid (GC) resistance in Crohn's disease (CD) and ulcerative colitis (UC) patients. We have developed a high-resolution DNA melting method that allows simultaneous identification of GR (BclI, N363S and ER22/23EK) and FKBP5 (rs3800373, rs1360780 and rs4713916) polymorphisms. Genotype frequencies were determined in 100 consecutive CD and 100 UC patients under GCs therapy (50 responders and 50 resisters). The variation of FKBP5 polymorphism rs4713916 (G/A), in the putative promoter region of FKBP5, is significantly associated with resistance to GC treatment in CD (responder ¼ 17% versus resister ¼ 35%; P ¼ 0.0043). No significant differences were found in UC patients. If these preliminary findings will be confirmed, the combination of GR and FKBP5 mutational analyses could help to identify subgroups of CD patients with higher chances to benefit from GC treatment.

Pharmacology and pharmacogenetics of prednisone and prednisolone in patients with nephrotic syndrome

“…For several diseases, which are treated with glucocorticoids, including nephrotic syndrome, altered levels of chaperone protein hsp90 were found in peripheral blood mononuclear cells from individuals with a steroid-resistant course of disease [94][95][96]. Although limited, some evidence exists about the association of polymorphisms in the gene encoding for one of the co-chaperones, FKBP5, with steroid resistance in Crohn's disease [97]. Interestingly, this could also hold true for nephrotic syndrome patients as well.…”

Clinical Pharmacokinetic and Pharmacodynamic Considerations in the Treatment of Ulcerative Colitis

“…Nevertheless, approximately 30% of IBD patients have a poor or absent clinical response to corticosteroids [57]. Abnormalities of the glucocorticoid receptor might be the cause of an absent response to corticosteroids.…”

“…Second, this low affinity may be caused by the existence of polymorphisms of the glucocorticoid receptor. However, the association between polymorphisms involving the glucocorticoid receptor and response to corticosteroid treatment in UC patients has not yet been demonstrated [57,59]. Additionally, in corticosteroid-naive IBD patients, Schottelius et al showed an increased expression of the glucocorticoid receptor and a decreased affinity to this receptor compared with a healthy control group [60].…”

Glucocorticoids in Pediatric Gastrointestinal Disorders

“…In a study considering the role of ER22/23EK in the variability of clinical response to GCs in IBD, no association was found between the ER22/23EK polymorphism and GC response in 119 pediatric patients [ 74 ]. These polymorphisms have been also studied in adult patients with IBD, but no correlation has been observed with GC-resistant phenotype, even when dividing patients into UC and CD groups [ 75 ].…”

“…Association with higher post-DEX cortisol levels and less cortisol suppression after a 1 mg DEX suppression test [ 69 ] Correlation with a better metabolic and cardiovascular health profi le and an increased survival [ 70 ] In 119 pediatric patients with IBD, no association with GC response [ 74 ] In adult IBD patients, no correlation with GC-resistant phenotype even when dividing patients into UC and CD [ 75 ] GR-9β (rs6198) Association of the haplotype consisting of TthIII I, ER22/23EK, and GR-9β-G with GC resistance, and with a more rapid disease progression [ 83 ] N363S (rs6195) Signifi cant correlation with ocular hypertension in 102 patients who underwent photorefractive keratectomy and received topical steroids [ 84 ] In 48 patients with Duchenne muscular dystrophy treated with prednisolone or defl azacort, correlation with a later age at loss of ambulation [ 85 ] No correlation with response to GCs in pediatric IBD patients [ 74 ] No correlation with response to GCs in adult IBD patients [ 75 ] BclI (rs41423247) In 119 pediatric patients with IBD, association with GC response [ 74 ] Unfavorable metabolic characteristics, such as increased body mass index and insulin resistance [ 87 ] the peripheral blood of patients with active UC as compared with patients with CD, 12 miRNAs signifi cantly increased and 1 miRNA signifi cantly decreased in the blood of patients with active UC compared with healthy controls, and 5 miRNAs signifi cantly increased and 2 miRNAs signifi cantly decreased in the blood of patients with active CD compared with healthy controls [ 103 ]. Paraskevi and colleagues recently identifi ed 11 miRNAs signifi cantly increased in CD and 6 miRNAs increased in UC blood samples compared with healthy controls [ 104 ]: These results confi rmed previous studies of IBD miRNA expression obtained in blood and/or tissue samples [ 98 , 105 ].…”